A Randomized, Double-Blind Evaluation of d -Cycloserine or Alprazolam Combined With Virtual Reality Exposure Therapy for Posttraumatic Stress Disorder in Iraq and Afghanistan War Veterans
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OBJECTIVE: The authors examined the effectiveness of virtual reality exposure augmented with D-cycloserine or alprazolam, compared with placebo, in reducing posttraumatic stress disorder (PTSD) due to military trauma. METHOD: After an introductory session, five sessions of virtual reality exposure were augmented with D-cycloserine (50 mg) or alprazolam (0.25 mg) in a double-blind, placebo-controlled randomized clinical trial for 156 Iraq and Afghanistan war veterans with PTSD. RESULTS: PTSD symptoms significantly improved from pre- to posttreatment across all conditions and were maintained at 3, 6, and 12 months. There were no overall differences in symptoms between D-cycloserine and placebo at any time. Alprazolam and placebo differed significantly on the Clinician-Administered PTSD Scale score at posttreatment and PTSD diagnosis at 3 months posttreatment; the alprazolam group showed a higher rate of PTSD (82.8%) than the placebo group (47.8%). Between-session extinction learning was a treatment-specific enhancer of outcome for the D-cycloserine group only. At posttreatment, the D-cycloserine group had the lowest cortisol reactivity and smallest startle response during virtual reality scenes. CONCLUSIONS: A six-session virtual reality treatment was associated with reduction in PTSD diagnoses and symptoms in Iraq and Afghanistan veterans, although there was no control condition for the virtual reality exposure. There was no advantage of D-cycloserine for PTSD symptoms in primary analyses. In secondary analyses, alprazolam impaired recovery and D-cycloserine enhanced virtual reality outcome in patients who demonstrated within-session learning. D-cycloserine augmentation reduced cortisol and startle reactivity more than did alprazolam or placebo, findings that are consistent with those in the animal literature.
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D-cycloserine administered with VRET for PTSD patients has been proven effective in reducing PTSD symptoms.
“VRET has also been augmented pharmacologically by administering D-cycloserine with VRET for PTSD patients. This combination has been proven effective in reducing PTSD symptoms (Rothbaum et al., 2014; Difede et al., 2014)”
From Virtual Reality exposure therapy in the treatment of public speaking anxiety and social anxiety disorder (2024) · cites this paper as Rothbaum et al., 2014
The Abstract Results report that PTSD symptoms improved during VRE across all treatment groups, including the D-cycloserine group. But they found no overall symptom advantage for D-cycloserine, and the Discussion calls its enhancement of VRE inconclusive. Because there was no VRE-only control, this paper does not establish that the combination itself was effective. (LLM, conf=0.89)
Experimental — accuracy not yet measuredClinically, individuals with PTSD have been shown to have alterations in stimulus generalization, fear inhibition, discrimination, and fear extinction.
“Clinically, individuals with PTSD have been show to have alterations in stimulus generalization (16), fear inhibition (29), discrimination, and fear extinction (38).”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [38]
Trauma imagery-potentiated startle responses in recently returned combat veterans from Iraq and Afghanistan were significantly reduced in individuals who previously received DCS before each of five sessions of virtual reality exposure therapy for PTSD.
“Finally, trauma imagery-potentiated startle responses in recently returned combat veterans from Iraq and Afghanistan were significantly reduced in individuals who previously received DCS before each of five sessions of virtual reality exposure therapy for PTSD (38).”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [38]
Trials of D-cycloserine to augment exposure therapy for PTSD have yielded mixed results: one found faster symptom reduction, one found a detrimental effect, and three found no effect.
“One study found evidence of a faster rate of symptom reduction 141 , while another reported a detrimental effect 142 , and three further trials found no effect 143-145 .”
From Post‐traumatic stress disorder: a state‐of‐the‐art review of evidence and challenges (2019) · cites this paper as [143]
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Seuling, P. D., Czernin, N. S., & Schiele, M. A. (2024) · Neuroscience Applied · doi:10.1016/j.nsa.2024.104074 · Cited by 28 · see citing works
“This combination has been proven effective in reducing PTSD symptoms (Rothbaum et al., 2014; Difede et al., 2014), with the supplementation of D-cycloserine increasing treatment efficacy over standard VRET in one trial (Difede et al., 2014).”
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Utility of Psychophysiological Metrics in Guiding Treatment of Trauma Symptoms: A Systematic Review
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Starting from something: augmenting exposure therapy and methods of inquiry
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Using experimental methodologies to assess posttraumatic stress
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- Authors
- Rothbaum, B. O., Price, M., Jovanovic, T., Norrholm, S. D., Gerardi, M., Dunlop, B., Davis, M., Bradley, B., Duncan, E. J., Rizzo, A., & Ressler, K. J.
- Affiliations
- University of Vermont (US)
- From the Trauma and Anxiety Recovery Program and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta; the Trauma Recovery Program and Mental Health Service, Department of Veterans Affairs Medical Center, Atlanta; the Department of Psychology, University of Vermont, Burlington; the Howard Hughes Medical Institute, Chevy Chase, Md.; and the Institute for Creative Technologies and the Department of Psychiatry and Behavioral Sciences, University of Southern...
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2014-06
- Volume
- 171
- Issue
- 6
- Pages
- 640-648
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC4115813
- OpenAlex
- W2160848506
- Cited by
- 388
- References
- 36
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 23 · 2023: 26 · 2022: 36 · 2021: 33 · 2020: 29 · 2019: 43 · 2018: 45 · 2017: 48 · 2016: 27 · 2015: 38 · 2014: 20
- FWCI
- 52.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense (W81XWH, W81XWH1011045)
- McCormick Foundation
- Pfizer
- Emory University
- National Alliance for Research on Schizophrenia and Depression
- University of Oxford
- National Institutes of Health (5u19mh069056-10, W81XWH)
- Genentech
- National Institute of Mental Health (U19-MH069056, 1R01MH70880-01-A2, R01MH094757, R01MH070880)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Physical Sciences › Computer Science › Human-Computer Interaction › Virtual Reality Applications and Impacts
- Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
- Keywords
- post-traumatic stress disorder, virtual reality exposure therapy, D-cycloserine, alprazolam, Iraq and Afghanistan veterans, military trauma, extinction learning, cortisol response, startle response, drug augmentation, PTSD treatment outcomes
- MeSH terms
- Adult, Alprazolam, Combined Modality Therapy, Cycloserine, Double-Blind Method, Extinction, Psychological, Female, Humans, Male, Psychiatric Status Rating Scales, Stress Disorders, Post-Traumatic, Anti-Anxiety Agents, Veterans, Treatment Outcome, Iraq War, 2003-2011, Afghan Campaign 2001-, Virtual Reality Exposure Therapy
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